The emerging risk of overdiagnosis in rheumatoid arthritis and polymyalgia rheumatica.

Overdiagnosis occurs when patients are diagnosed with a disease that would otherwise never have affected the quality or duration of their lives. This often happens unintentionally through well-meaning screening programmes that aim to detect diseases during so-called subclinical stages. Recently, it has been suggested that patients with polymyalgia rheumatica should be screened for giant cell arteritis to identify those at higher risk of relapse or vascular complications. Screening for interstitial lung disease for patients with rheumatoid arthritis has also been recommended to identify patients who could benefit from pulmonary interventions. These potential benefits must be weighed against foreseeable harms. Such harms include the uncovering of incidental findings that necessitate additional medical follow-up, the financial costs associated with screening initiatives, the risk of overtreatment through increased immunosuppression in patients who might not have otherwise required it, and the psychosocial burden of a new diagnosis. Randomised clinical trials and prospective cohort studies of screening interventions should be conducted to establish the risks and benefits and identify patients most likely to benefit from them. This Viewpoint covers risks that overdiagnosis presents to the field of rheumatology, with focus on rheumatoid arthritis and polymyalgia rheumatica.

Positive and negative controls in rheumatology research.

Observational research from large population databases may be affected by unmeasured confounding and time-related biases, such as immortal time bias. Modern causal inference practice applies propensity score-based methods, new-user designs, and other strategies to mitigate bias. The degree to which these methodologic approaches adequately address bias for any particular study may be difficult to measure. Recently, the incorporation of positive and negative controls has been identified as a means to assess for the impacts of residual confounding and/or time-related biases. The objective of this commentary is to describe the role of positive and negative controls in observational research. We offer recommendations for incorporating controls into critical appraisal and observational research projects.

The State of Patient-Reported Outcome Measures in Rheumatology.

OBJECTIVE: We sought to evaluate the quality and timeliness of patient-reported outcome (PRO) measure reporting, which have not been previously studied. METHODS: Clinical trials that informed new US Food and Drug Administration (FDA) approvals for the first rheumatological indication between 1995 and 2021 were identified. Data were recorded to determine whether collected PROs were published, met minimum clinically important difference (MCID) or statistical significance (P < 0.05) thresholds, and were consistent with Consolidated Standards of Reporting Trials (CONSORT)-PRO standards. Hazard ratios and Kaplan-Meier estimate were used to assess the time from FDA approval to PRO publication. RESULTS: Thirty-one FDA approvals corresponded with 110 pivotal trials and 262 reported PROs. Of the 90 included studies, 1 (1.1%) met all 5 recommended items, 10 (11.1%) met 4 items, 17 (18.9%) met 3 items, 21 (23.3%) met 2 items, 26 (28.9%) met 1 item, and 15 (16.7%) met none of the reporting standards. Most PROs met MCID thresholds (149/262; 56.9%) and were statistically significant (223/262; 85.1%). Of our subset analysis, one-third of PROs were not published upfront (70/212; 33%) and 1 of 9 (22/212; 10.4%) remained unpublished ≥ 4 years after initial trial reporting. Publication rates were highest for the Health Assessment Questionnaire-Disability Index (97.4%) and lowest for the 36-item Short Form Health Survey (81.8%). Less than half of these published PROs met MCID and statistical significance thresholds (94/212; 44.3%). CONCLUSION: One in 9 PROs remained unpublished for ≥ 4 years after initial trial reporting, and compliance with CONSORT-PRO reporting guidelines was poor. Efforts should be made to ensure PROs are adequately reported and expeditiously published.

Impact of Glucocorticoid Dose on Complete Response, Serious Infections, and Mortality During the Initial Therapy of Lupus Nephritis: A Systematic Review and Meta-Analysis of the Control Arms of Randomized Controlled Trials.

OBJECTIVE: Our objective was to evaluate the effect of glucocorticoid regimens on renal response, infections, and mortality among patients with lupus nephritis (LN). METHODS: We performed a systematic review and meta-analysis of the control arms of randomized clinical trials (RCTs). We included RCTs of biopsy-proven LN that used a protocolized regimen of glucocorticoids in combination with mycophenolic acid analogs or cyclophosphamide and reported the outcomes of complete response (CR), serious infections, and death. The starting dosage of glucocorticoids, tapering method, and administration of glucocorticoid pulses were abstracted. Meta-analysis of proportions, meta-regression, and subgroup meta-analysis were performed at 6 and 12 months for all outcomes. RESULTS: Fifty RCT arms (3,231 patients with LN) were included. The predicted rates of CR, serious infections, and death when starting on oral prednisone at 25 mg/day without pulses were 19.5% (95% confidence interval [CI] 7.3-31.5), 3.2% (95% CI 2.4-4.0), and 0.2% (95% CI 0.0-0.4), respectively. Starting on prednisone at 60 mg/day (without pulses) increased the rates to 34.6% (95% CI 16.9-52.3), 12.1% (95% CI 9.3-14.9), and 2.7% (95% CI 0.0-5.3), respectively. Adding glucocorticoid pulses increased the rates of CR and death but not serious infections. We observed a dose-response gradient between the initial glucocorticoid dosage and all the outcomes at six months after accounting for the administration of glucocorticoid pulses, underlying immunosuppressant, and baseline proteinuria. CONCLUSION: A higher exposure to glucocorticoids during the initial therapy of LN was associated with better renal outcomes at the cost of increased infections and death.

Risk of Neuroinflammatory Diseases Among New Recipients of Biologic and Targeted Synthetic Disease-Modifying Antirheumatic Drugs.

OBJECTIVE: Neuroinflammatory adverse events have been observed among new users of tumor necrosis factor (TNF) inhibitors. No studies to date have compared the real-world risk of TNFs with other new users of biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). The objective of this study is to describe the risk of neuroinflammatory disease after initiation b/tsDMARDs. METHODS: This new user comparative effectiveness cohort study used a large US-based electronic health records database to describe the unadjusted incidence of neuroinflammatory adverse events over a 3-year period. The cohort included patients with rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, or ulcerative colitis initiating treatment with a TNF inhibitor (n = 93,661) or other b/tsDMARD (n = 38,354). RESULTS: Among 132,015 patients included in the analysis, the most common first biologic agent was a TNF inhibitor; the unadjusted incidence of neuroinflammatory events was numerically lower among new users of TNF inhibitors (incidence 1.34 per 1,000 patient-years) as compared with the combined non-TNF group (1.69 per 1,000 patient-years). There was no significant association between TNF exposure and neuroinflammatory events as compared with the combined non-TNF b/tsDMARDs overall (hazard ratio 1.01; 95% confidence interval 0.75-1.36) and within each disease group. CONCLUSION: The overall risk of neuroinflammatory events among new users of TNF inhibitors did not differ substantially as compared with new users of other b/tsDMARDs. Meta-analyses of randomized trials should be conducted to corroborate these findings, which may be affected by channeling bias.

Fragility of randomised controlled trials for systemic lupus erythematosus and lupus nephritis therapies.

OBJECTIVE: We aimed to evaluate the robustness of phase III randomised controlled trials (RCTs) for SLE and lupus nephritis (LN) using the fragility index (FI), the reverse FI (RFI) and the fragility quotient (FQ). METHODS: We searched for phase III RCTs that included patients with active SLE or LN. Data on primary endpoints, total participants and the number of events for each arm were obtained. We calculated the FI score for RCTs with statistically significant results (number of patients required to change from event to non-event to make the study lose statistical significance), the RFI for RCTs without statistically significant results (number of patients required to change from non-event to event to make study gain statistical significance) and the FQ score for both (FI or RFI score divided by the sample size). RESULTS: We evaluated 20 RCTs (16 SLE, four LN). The mean FI/RFI score was 13.6 (SD 6.6). There were nine RCTs with statistically significant results (seven SLE, two LN), and the mean FI score was 10.2 (SD 6.2). The lowest FI was for the ILLUMINATE-2 trial (FI=2), and the highest FI was for the BLISS-52 trial (FI=17).Twelve studies had non-statistically significant results (10 SLE, two LN) with a mean RFI score of 15.6 (SD 6.1). The lowest RFI was for the ILLUMINATE-1 trial (RFI=4), and the highest RFI was for the TULIP-1 trial (RFI=27). The lowest FQ scores were found in the ILLUMINATE trials and the highest in the Rituximab trials (EXPLORER and LUNAR), meaning that the last ones were the most robust results after accounting for sample size. CONCLUSIONS: The evidence of therapies for patients with SLE and LN is derived mostly from fragile RCTs. Clinicians and trialists must be aware of the fragility of these RCTs for clinical decision-making and designing trials for novel therapeutics.

Incidence of Pneumocystis Jiroveci Pneumonia in Patients With ANCA-Associated Vasculitis Initiating Therapy With Rituximab or Cyclophosphamide.

OBJECTIVE: This manuscript assesses the incidence of Pneumocystis jiroveci pneumonia (PJP) among patients receiving contemporary treatment regimens for antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and adverse events associated with PJP prophylaxis. METHODS: Incident users of rituximab or cyclophosphamide for AAV were identified in the TriNetX electronic health records database from 2011 to 2022. The incidence rates (IRs) of PJP in the first 6 months of induction therapy with rituximab and/or cyclophosphamide and during postinduction maintenance therapy with rituximab were calculated. Cox proportional hazard models were used to estimate hazard ratios (HRs) and confidence intervals (CIs) for the risk of adverse events commonly associated with PJP prophylaxis. RESULTS: We identified 1,461 AAV cases who received induction therapy with rituximab (69.7%), cyclophosphamide (18.9%), or both (11.4%). Prophylaxis prescribed within 30 days of induction included trimethoprim-sulfamethoxazole (30.7%), atovaquone (5.4%), dapsone (3.8%), and pentamidine (0.8%). During induction therapy, 10 cases of PJP were identified (IR 15.0 cases per 1,000 patient-years); no deaths occurred. In adjusted analyses, those who received prophylaxis had a higher risk of leukopenia (HR 3.1; 95% CI 1.1-8.6), rash (HR 1.9; 95% CI 1.0-3.6), and nephropathy (HR 2.6; 95% CI 1.3-5.1) than those who did not. During rituximab maintenance therapy (n = 709), five cases of PJP were identified (IR 2.1 cases per 1,000 person-years), one of whom died during the hospitalization associated with a PJP diagnosis. CONCLUSION: Rates of PJP in patients with AAV were lower than previously observed, and few cases occurred during rituximab maintenance therapy. PJP prophylaxis was associated with adverse events.

Recommendations for early referral of individuals with suspected polymyalgia rheumatica: an initiative from the international giant cell arteritis and polymyalgia rheumatica study group.

OBJECTIVE: To develop international consensus-based recommendations for early referral of individuals with suspected polymyalgia rheumatica (PMR). METHODS: A task force including 29 rheumatologists/internists, 4 general practitioners, 4 patients and a healthcare professional emerged from the international giant cell arteritis and PMR study group. The task force supplied clinical questions, subsequently transformed into Population, Intervention, Comparator, Outcome format. A systematic literature review was conducted followed by online meetings to formulate and vote on final recommendations. Levels of evidence (LOE) (1-5 scale) and agreement (LOA) (0-10 scale) were evaluated. RESULTS: Two overarching principles and five recommendations were developed. LOE was 4-5 and LOA ranged between 8.5 and 9.7. The recommendations suggest that (1) each individual with suspected or recently diagnosed PMR should be considered for specialist evaluation, (2) before referring an individual with suspected PMR to specialist care, a thorough history and clinical examination should be performed and preferably complemented with urgent basic laboratory investigations, (3) individuals with suspected PMR with severe symptoms should be referred for specialist evaluation using rapid access strategies, (4) in individuals with suspected PMR who are referred via rapid access, the commencement of glucocorticoid therapy should be deferred until after specialist evaluation and (5) individuals diagnosed with PMR in specialist care with a good initial response to glucocorticoids and a low risk of glucocorticoid related adverse events can be managed in primary care. CONCLUSIONS: These are the first international recommendations for referral of individuals with suspected PMR, which complement the European Alliance of Associations for Rheumatology/American College of Rheumatology management guidelines for established PMR.

Twenty-five years of novel drug approvals in rheumatology.

The field of rheumatology has experienced dozens of novel drug approvals in the past two and a half decades, but the regulatory mechanisms underpinning these decisions are not well understood. In the USA, the Food and Drug Administration (FDA) evaluates the safety and efficacy of novel drugs through the New Drug Application (NDA) process. When additional content expertise is required to evaluate scientific or technical matters, the FDA may convene Human Drug Advisory Committees. To better understand the landscape of rheumatology NDAs and the FDA use of advisory committees, we performed a review of all rheumatic disease drug applications from 1996 to 2021 that were granted approval by the FDA. Our review identified 31 NDAs, seven of which utilized an advisory committee. The indications for using advisory committees and their influence on ultimate approvals was not clear. Recommendations to improve transparency and increase public trust in FDA decisions are provided.

Giant Cell Arteritis and Polymyalgia Rheumatica: Treatment Approaches and New Targets.

Prolonged glucocorticoid tapers have been the standard of care for giant cell arteritis (GCA) and polymyalgia rheumatica (PMR), but recent advancements have improved outcomes for patients with GCA while reducing glucocorticoid-related toxicities. Many patients with GCA and PMR still experience persistent or relapsing disease, and cumulative exposure to glucocorticoids for both diseases remains high. The objective of this review is to define current treatment approaches as well as new therapeutic targets and strategies. Studies investigating inhibition of cytokine pathways, including interleukin-6, interleukin-17, interleukin-23, granulocyte-macrophage colony-stimulating factor, Janus kinase-signal transduction and activator of transcription, and others, will be reviewed.

Unpublished clinical trials of common rheumatic diseases.

OBJECTIVES: Randomized controlled trials (RCTs) provide high-quality evidence for treatment efficacy, but many RCTs remain unpublished. The objective of this study was to describe the proportion of unpublished RCTs in five rheumatic diseases and to identify factors associated with publication. METHODS: Registered RCTs for five rheumatic diseases (SLE, vasculitis, spondyloarthritis, SS and PsA) with over 30 months since study completion were identified using ClinicalTrials.gov. Index publications were identified by NCT ID numbers and structured text searches of publication databases. The results of unpublished studies were identified in abstracts and press releases; reasons for non-publication were assessed by surveying corresponding authors. RESULTS: Out of 203 studies that met eligibility criteria, 17.2% remained unpublished, representing data from 4281 trial participants. Higher proportions of published trials were phase 3 RCTs (57.1% vs 28.6% unpublished, P < 0.05) or had a positive primary outcome measure (64.9% vs 25.7% unpublished, P < 0.001). In a multivariable Cox proportional hazards model, a positive outcome was independently associated with publication (hazard ratio 1.55; 95% CI: 1.09, 2.22). Corresponding authors of 10 unpublished trials cited ongoing preparation of the manuscript (50.0%), sponsor/funder issues (40.0%) and unimportant/negative result (20.0%) as reasons for lack of publication. CONCLUSIONS: Nearly one in five RCTs in rheumatology remain unpublished 2 years after trial completion, and publication is associated with positive primary outcome measures. Efforts to encourage universal publication of rheumatology RCTs and reanalysis of previously unpublished trials should be undertaken.

Is there a role for Pneumocystis jiroveci pneumonia prophylaxis in giant cell arteritis or polymyalgia rheumatica?

BACKGROUND: Pneumocystis jiroveci pneumonia (PJP) is an opportunistic fungal infection that affects immunocompromised patients. The objective of this study was to describe the incidence of PJP among patients with giant cell arteritis (GCA) or polymyalgia rheumatica (PMR). METHODS: A retrospective cohort study of incident cases of GCA and PMR was conducted using claims data from the TriNetX database to describe the incidence of PJP during the first 6 months of therapy. Additionally, a systematic review was performed to identify other publications describing PJP among patients with GCA or PMR. RESULTS: During 547 patient-years of follow-up time, no cases of PJP were identified among 1,168 cases of GCA (incident rate 0 per 1,000 person-years); during 7,446 patient-years of follow up time, one case of PJP was identified out of 15,575 cases of PMR (incident rate 0.07 cases per 1,000 patient-years). This patient was alive at last follow up. Our systematic review identified 1 case-control study, 4 cohort studies, and 18 case series / case reports of PJP among patients with GCA or PMR. The incident rate of PJP was reported from one additional study for GCA and was estimated at 0.08 cases per 1,000 person years; no additional cohort studies were identified for patients with PMR. Over the entirety of the published literature, the total number of cases identified among case series and case reports was 33, from which 4 total deaths were identified. CONCLUSIONS: Patients with newly diagnosed GCA or PMR rarely develop PJP. Existing data does not support routine prescribing of PJP prophylaxis for either group of patients.

Association Between Neighborhood Deprivation and Number of Rheumatology Providers.

OBJECTIVE: Geographic disparities in the distribution and practice patterns of rheumatology providers may negatively impact patients with rheumatic diseases. The objective of this study was to describe the distribution of rheumatologists with respect to the Area Deprivation Index (ADI) and to identify differences in practice patterns among Medicare Part D rheumatologist prescribers. METHODS: We identified 5,882 rheumatologists who served a mean ± SD of 280 ± 208 Medicare Part D beneficiaries per year. In a Poisson regression model of the number of rheumatologists and the ADI of their practice location, for every increase of 10 on the ADI scale (range 0-100; higher = higher deprivation), there were 20.3% fewer rheumatologists (P < 0.001), resulting in 2.1 times as many rheumatologists per 100,000 people in the first ADI quintile when compared to the fifth ADI quintile. RESULTS: The number of rheumatologists peaked in 2016 and decreased steadily thereafter across all quintiles. The prescribing rate per 100 beneficiaries was significantly different between quintiles across all studied drug classes except for opioids, but the trends were inconsistent and of unclear clinical significance. CONCLUSION: Rheumatologists tended to practice in areas with less deprivation, resulting in twice as many rheumatologists per 100,000 people in the quintile of lowest deprivation as opposed to the quintile with the highest deprivation. Public policy makers should be aware of these data and take steps to mitigate disparities in access to care as the rheumatology workforce shrinks.

Unintentional unblinding in rheumatic disease trials.

The practice of blinding treatment assignment in randomised controlled trials mitigates important biases in observational studies. Unblinding, whereby study participants or investigators become aware of treatment assignments, is an important threat to the validity of trial results. Rheumatology studies might be particularly susceptible to unblinding because rheumatic disease therapies often cause high rates of idiosyncratic side-effects and frequently rely on subjective endpoints. Despite this susceptibility, the degree to which unblinding occurs in randomised controlled trials in rheumatic diseases has rarely been assessed during trials or acknowledged as a limitation. Rheumatologists should be aware of this important threat to the validity of trial results, assessments of unblinding should be undertaken, and strategies to prevent unblinding should be deployed when feasible.